S.J. Strada and G.A. Robison,     Program in Pharmacology, University of Texas Medical School at Houston, Houston, Texas

Publisher Summary

Adenosine 3’, 5’-monophosphate (cyclic AMP) is formed from ATP through the action of adenylyl cyclase, which seems to be an integral component of the cell membrane in most cells. Hormones appear to stimulate the enzyme by interacting with specific receptors on the external surface of the membrane. Calcium is involved in several ways; it is required for cyclase activation by at least one hormone (ACTH), and there is evidence that some hormones can influence calcium transport independently of their effect on cyclise. Fluoride stimulates adenylyl cyclise activity in broken cell preparations of most eukaryotic cells, but so far, this has not led to any important insights into the mechanism of hormonal stimulation. Cyclic AMP is metabolized to 5’-AMP under the catalytic influence of one or more phosphodiesterases. Phosphohpids, ions, and one or more endogenous proteins are involved in regulating phosphodiesterase activity, and cyclic AMP itself appears capable of inducing the formation of at least one isozyme. Most of the physiologically important effects of cyclic AMP in higher forms are the result of protein kinase activation. Cyclic AMP-dependent protein kinases are composed of catalytic and regulatory subunits.

I Introduction

Adenosine 3′,5′-monophosphate (cyclic AMP) was discovered in 1956 in the course of endocrinological research (see Sutherland and Rall, 1960, for an early review). Most of the research on this substance for the next 10 years or so was concerned directly or indirectly with its role as a regulator of differentiated eukaryotic cell function. It was shown first to mediate the hepatic glycogenolytic effect of glucagon and epinephrine, and was eventually recognized as a second messenger mediating many of the effects of a variety of other hormones, including ACTH (adrenocorticotropic hormones), TSH (thyroid-stimulating hormone), vasopressin, luteinizing hormone, MSH (melanocyte-stimulating hormone), and parathyroid hormone. This aspect of the subject has been discussed in a number of recent monographs and review articles (e.g., Robison et al., 1971 a,b; Hardman et al., 1971; Cheung, 1972; Gill, 1972; Major and Kilpatrick, 1972; Greengard et al., 1972a; Sutherland, 1972).

One of the reasons for the slow initial progress in understanding the role of cyclic AMP was that methodology was difficult, but this is no longer the most important limiting factor (Greengard et al., 1972b; Chasin, 1972). Cyclic AMP has now transcended its endocrinological beginning and has been shown to function in almost all animal species, including bacteria and other unicellular organisms. In Escherichia coli and other gram-negative bacteria, cyclic AMP appears to be required for the synthesis of a number of inducible enzymes, and the ability of glucose to suppress cyclic AMP formation appears to account satisfactorily for catabolite repression (Pastan and Perlman, 1972). Cyclic AMP has also been implicated in lysogeny (Hong et al., 1971) and bacterial transformation (Wise et al., 1973). In certain species of cellular slime molds, cyclic AMP appears to be responsible for initiating the aggregation of slime mold amebae, leading to the formation of a multicellular organism (Bonner, 1971).

Evidence has now begun to accumulate to suggest that cyclic AMP may also play an important role during the growth and development of higher organisms. Although data are presently insufficient to define this role precisely, it would appear that in some types of cells reduced levels of cyclic AMP are needed to permit rapid cell division, whereas higher levels are associated with differentiation (Weiss and Strada, 1973). Changes in cyclic AMP during the cell cycle are now being explored (Willingham et al., 1972; Burger et al., 1972), and an important complementary role for cyclic GMP (guanosine 3′,5′-monophosphate) has been suggested (Hadden et al., 1972). It now seems possible that reduced levels of cyclic AMP or perhaps increased levels of cyclic GMP are involved in a number of proliferative disorders, including psoriasis (Voorhees et al., 1972) and certain forms of cancer (Otten et al., 1972). Cyclic nucleotides may also play an important series of roles during the immune response (see, for example, Orange et al., 1971; Parker, 1972; Hadden et al., 1972; Bourne et al., 1973), although it may be some time before these roles become clarified.

It is no longer possible to discuss intelligently all aspects of cyclic nucleotide research in a single review article. Our purpose in this review will be to summarize what is known about the formation, metabolism, and action of cyclic AMP, with major emphasis on eukaryotic cells. In all cells studied, cyclic AMP is formed from ATP through the catalytic influence of adenylyl cyclase, and is metabolized to 5′-AMP under the influence of one or more phosphodiesterases (Fig.1). The intracellular level of cyclic AMP is therefore determined by the rates of these reactions, as well as by the rate at which it is released into the extracellular space. Most of the effects of cyclic AMP are poorly understood, but the glycogenolytic and lipolytic effects have been shown to involve the activation of a protein kinase. This may be the mechanism of many and perhaps most of the physiologically important effects of cyclic AMP in differentiated eukaryotic cells.

II Adenylyl Cyclase